Gene-rich pufferfish DNA decoded

A substantial short cut to the biologically important information embedded in the human genome has been taken by an international research consortium with the completion of a draft sequence of the genome of the Japanese pufferfish Fugu rubripes

October 29—Although the Fugu genome contains essentially the same genes and regulatory sequences as the human genome, it carries those genes and regulatory sequences in approximately 365 million bases as compared to the 3 billion bases that make up human DNA. With far less so-called "junk DNA" to sort through, finding genes and controlling sequences in the Fugu genome should be a much easier task. The information can then be used to help identify these same elements in the human genome. This Fugu draft sequence is the first public assembly of an animal genome by the whole genome shotgun sequencing method.

The consortium that sequenced the Fugu genome was led by the U.S. Department of Energy's Joint Genome Institute (JGI) in Walnut Creek, California, and the Singapore Biomedical Research Council's Institute for Molecular and Cell Biology (IMCB). Also part of the consortium is the MRC UK Human Genome Mapping Resource Centre (HGMP-RC) in Cambridge, England, the Cambridge University Department of Oncology, and the Institute for Systems Biology in Seattle, Washington. The consortium's sequencing efforts were bolstered by two U.S. companies, Celera Genomics, Rockville, Maryland, and Myriad Genetics, Inc., Salt Lake City, Utah.

The Fugu genome project was initiated in 1989 by Sydney Brenner in Cambridge, England, along with his colleagues Greg Elgar, Samuel Aparicio, and Byrappa Venkatesh. Brenner is known for his work in molecular genetics and for the establishment of C. elegans (the worm) as a model organism. Formed in November 2000, the International Fugu Genome Consortium represents one of the largest international genome-sequencing projects since the historic Human Genome Project. The goal of the consortium is to sequence, assemble, annotate, and ultimately finish the Fugu genome, and disseminate the information to the greater research community.

Brenner, now a Distinguished Professor at The Salk Institute for Biological Studies in San Diego and Board Director of the Singapore Biomedical Research Council, said, "This represents the culmination of more than a decade of work in Cambridge and Singapore. Without JGI's initiative and Singapore's strong support, the project would have languished. We already know that it will illuminate the human genome sequence and help us to understand it."

"All organisms are related," said Trevor Hawkins, Director of the Joint Genome Institute, which is one of the largest publicly funded genome sequencing centers in the world and itself a consortium operated jointly by the three University of California-managed DOE national laboratories, Lawrence Berkeley, Lawrence Livermore, and Los Alamos.

"Although the Fugu genome is only one-eighth the size of our human genome, it has a similar complement of genes. Yet we know very little about the structure of those genes and how they are turned on and off. That's why we're sequencing genomes of microbes, sea squirts and now Fugu-because these comparative genomics programs are key to understanding the biology of the human genome."

A whole genome shotgun strategy was employed to sequence the Fugu genome. "We first chopped the genome up into pieces that are small enough to sequence," said Dan Rokhsar, Associate Director for Computational Genomics at the JGI. "The challenge was then to reassemble the genome by putting together nearly four million of these overlapping fragments-in the same way that you'd put together a giant jigsaw puzzle."

Solving this puzzle was made possible by a new computational algorithm, JAZZ, that has been developed at JGI to handle large genome sequencing projects. This method has also been implemented at the DOE's National Energy Research Scientific Computing Center (NERSC)-the world's largest supercomputer dedicated to unclassified research.

Chris Tan, founding Director of IMCB, says that the draft Fugu genome will yield much more accurate estimates of the gene repertoire in humans. "We will also now be able to refine many of the features of the non-coding regions that may prove to have regulatory control over genes expressed in the human genome."

Singapore IMCB is already leveraging the genome sequence through the creation of a live Fugu genome bioinformatics analysis pipeline producing annotations and comparisons for the community. Tan anticipates that over the next few years the Singapore group and the Institute for Systems Biology will finish selected regions of the genome, based upon their biology programs.

Tan added, "The IMCB's participation in the Consortium and contribution to this important project is testimony that Singapore has a key role to play in the international biomedical sciences scene."

The Consortium intends to publish an initial analysis of the draft Fugu genome early next year.

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